Hyperproliferative diseases, such as, for example, cancer are generally characterized by uncontrolled cellular proliferation and/or disruption in programmed cell death. The loss of a cell's ability to control cellular proliferation is often caused by genetic damage to the cellular pathways responsible for regulating cellular functions, including but not limited to, for example, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. As a result, one approach to treating hyperproliferative diseases has involved targeting at least one protein involved in regulating these cellular functions.
The protein kinases are at least one class of proteins that has been identified as playing an important role in regulating cellular functions. Indeed, many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. Such diseases include but are not limited to autoimmune diseases, bone diseases, inflammatory diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone related diseases.
The protein kinases are a large and diverse group of enzymes that are divided into groups based on the particular amino acids (serine/threonine, tyrosine, lysine and histidine) that a particular kinase targets. For example, receptor and non-receptor tyrosine kinases target tyrosine kinase and cyclin dependent kinases (CDKs) and mitogen activated protein kinases (MAPKs) target both tyrosine and serine/threonine.
Exemplary protein kinases, include, but are not limited to, for example, receptor tyrosine kinases (RTKs), such as, for example, growth factors including, for example, type III receptor tryrosine kinase (Flt3); non-receptor tyrosine kinases, such as, for example, Src kinases including, for example, Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk, Btk kinases, Csk kinases, ZAP70 kinases, and Kak kinases; serine/threonine kinases, such as, for example, p90 ribosomal S6 kinases (RSK), including, for example, RSK1/p90Rsk, RSK2, RSK3, and RSK4, checkpoint protein kinases, including, for example, CHK1 and CHK2, AURORA kinases, including, for example, aurora-A, aurora-B, and aurora-C, and Glycogen synthase kinase 3 (GSK3); cyclin dependent kinases (CDKs) including, for example, CDK1, CDK2, CDK4, CDK5, CDK6, CDK 7, and cell division control 2 protein (CDC2); and mitogen-activated protein kinases (MAPKs), such as, for example, mitogen-activated protein kinase 1 (ERK), MAPK3, MAPK7, mitogen-activated protein kinase 8 (JNK1), mitogen-activated protein kinase 14 (p38 alpha), MAPK 10, JNK 3 alpha protein kinase, stress-activated protein kinase JNK 2, and MAPK 14.
More recently, the Aurora kinases were discovered to be involved in the growth of various types of cancer cells, and as a result are being targeted to develop potential cancer treatments. Accordingly, efforts have been undertaken to develop Aurora kinase inhibitors that are therapeutically effective against cancer cells.